Over the last year, we have begun to investigate the role of nuclear transcription factors in controlling proliferation and transformation of human breast epithelial cells. We have demonstrated that the Jun and Fos families of transcription factors are expressed in a variety of nontumorigenic and tumorigenic breast epithelial cell lines, and have shown that Jun and Fos RNA expression, and transcriptional activating activity are stimulated by a variety of growth factors, and also by TPA. In addition, an inhibitor of Jun and Fos transactivating activity which effec- tively suppresses transcriptional activation in rat ~broblasts also inhibits Jun and Fos activity in human breast epithelial cells. Studies are now ongoing to determine if this inhibitor is capable of inhibiting the proliferation or transformation of these human breast epithelial cells. Additional ongoing studies include the characterization of other transcription factors in human breast epithelial cells. We are presently studying the members of the CREB family which regulate the cellular response to cyclic AMP, and the C/EBP family which are involved in regulating the cellular response to calcium. A detailed characterization of their expression and activity in human mammary cells will allow us to determine the relative role of each of these transcription factor families in controlling cellular proliferation and transformation. Once the activities of these transcription factors are well characterized, we will modulate their activity using inhibitors speci~c for each family of transcription factors. By interfering with transcription factor function, we may be able to block signal transduction pathways at a distal point where the signals from multiple growth factors converge. If these speci~c transcription factor inhibitors affect proliferation or transformation in human breast cells, such inhibitors might be promising chemopreventative agents.